Supplementary Material for: Higher risk of proteinuria with atezolizumab plus bevacizumab than lenvatinib in first-line systemic treatment for hepatocellular carcinoma

Introduction: Proteinuria presents a challenging complication during systemic therapy for hepatocellular carcinoma (HCC). This study aims to identify risk factors for proteinuria in patients with HCC treated with atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic treatment.
Methods: A retrospective analysis was conducted on 622 consecutive patients with unresectable HCC who received Atezo/Bev or LEN as first-line systemic treatment between October 2013 and October 2022. Cumulative incidence of proteinuria was estimated using Kaplan–Meier curves and compared using log-rank tests. Risk factors for proteinuria were identified using Cox proportional-hazard models, along with propensity score-matched and subgroup analyses.
Results: Among 367 patients treated with Atezo/Bev and 255 with LEN, the cumulative incidence of proteinuria at 12 months was 27.5%. In the multivariable analysis, Atezo/Bev treatment (HR, 1.57; 95% CI, 1.03–2.42), diabetes (HR, 1.64; 95% CI, 1.03–2.61), Child–Pugh class B (HR, 3.43; 95% CI, 1.34–8.78), macrovascular invasion (MVI; HR, 1.58; 95% CI, 1.04–2.38), and an estimated glomerular filtration rate ≤60 mL/min/1.73 m2 (HR, 3.21; 95% CI, 1.84–5.62) were identified as risk factors for proteinuria. A higher risk of proteinuria in Atezo/Bev patients compared with LEN was consistently observed in the PS-matched cohort, particularly pronounced in subgroups with MVI (HR, 2.84; 95% CI, 1.23–6.54) compared with those without MVI (HR, 1.31; 95% CI, 0.69–2.47).
Conclusions: Patients treated with Atezo/Bev as first-line systemic treatment for HCC exhibited a higher risk of proteinuria compared with those with LEN, particularly when accompanied by MVI.

引言：蛋白尿（Proteinuria）是肝细胞癌（hepatocellular carcinoma, HCC）全身治疗期间极具挑战性的并发症。本研究旨在探讨接受阿替利珠单抗联合贝伐珠单抗（atezolizumab plus bevacizumab, Atezo/Bev）或仑伐替尼（lenvatinib, LEN）作为一线全身治疗的HCC患者发生蛋白尿的危险因素。
方法：本研究对2013年10月至2022年10月期间接受Atezo/Bev或LEN作为一线全身治疗的622例连续纳入的不可切除HCC患者进行了回顾性分析。采用Kaplan-Meier曲线（Kaplan–Meier curves）估算蛋白尿的累积发生率，并通过对数秩检验（log-rank tests）进行组间比较。采用Cox比例风险模型（Cox proportional-hazard models）结合倾向得分匹配分析与亚组分析，筛选蛋白尿发生的危险因素。
结果：在367例接受Atezo/Bev治疗和255例接受LEN治疗的患者中，蛋白尿12个月累积发生率为27.5%。多变量分析显示，Atezo/Bev治疗（HR=1.57，95% CI：1.03~2.42）、糖尿病（HR=1.64，95% CI：1.03~2.61）、Child-Pugh B级（HR=3.43，95% CI：1.34~8.78）、大血管侵犯（macrovascular invasion, MVI；HR=1.58，95% CI：1.04~2.38）以及估算肾小球滤过率（estimated glomerular filtration rate, eGFR）≤60 mL/min/1.73 m²（HR=3.21，95% CI：1.84~5.62）均为蛋白尿发生的独立危险因素。在倾向得分匹配队列中，Atezo/Bev治疗患者的蛋白尿风险始终高于LEN治疗患者，其中合并MVI的亚组（HR=2.84，95% CI：1.23~6.54）的风险升高尤为显著，而未合并MVI的亚组（HR=1.31，95% CI：0.69~2.47）则未观察到明显差异。
结论：与接受LEN一线全身治疗的HCC患者相比，接受Atezo/Bev一线全身治疗的患者蛋白尿风险更高，尤其是合并大血管侵犯的患者。